A Novel Maturation Equation for Hepatic Clearance Across Preterm, Term Neonates, Children, and Adults: Application to Paracetamol and Its Metabolite.

IF 2.3 4区 医学
Yunjiao Wu, Swantje Völler, Sebastiaan C Goulooze, Karel Allegaert, Catherine M T Sherwin, Anne van Rongen, Daniëlla W E Roofthooft, Sinno H P Simons, Dick Tibboel, Robert B Flint, John N van den Anker, Catherijne A J Knibbe
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Abstract

A preterm and term neonate to adult (PTNA) maturation equation was introduced recently to describe the glomerular filtration rate maturation from birth to adulthood for neonates of varying gestational age. This study aims to evaluate the newly developed PTNA equation against common maturation approaches like allometric scaling (AS0.75), the AS0.75 plus postmenstrual age (PMA)-based Emax (AS0.75 + PMA) equation, and the bodyweight dependent exponent equation (BDE) for the maturation of three hepatic pathways of paracetamol (PCM) from preterm and term neonates up to adults. A population pharmacokinetic analysis was conducted with pooled plasma and urine data of PCM, PCM-glucuronide (PCM-GLU), PCM-sulfate (PCM-SULF), and PCM-oxidative metabolites (PCM-OXI) (number of observations:6428) from 298 subjects, including preterm and term neonates, infants, children, and adults. PTNA, AS0.75, AS0.75 + PMA, and BDE were evaluated separately to describe the formation clearance of each PCM metabolite. Results indicated that the PTNA equation best described the formation clearance of PCM-GLU, outperforming the BDE and AS0.75 + PMA equations in both statistical and graphical evaluation metrics and inter-individual variability reduction. For PCM-SULF and PCM-OXI, the PTNA equation also had the best performance, but the improvements were smaller. The final model described the PK of PCM and its metabolites adequately among subpopulations as indicated by diagnostic plots. In conclusion, the PTNA maturation equation best describes the maturation of all hepatic elimination pathways of PCM. It can, as such, be potentially applied to other drugs and pathways when data from both preterm and term neonates and older children are part of the PK analysis.

早产儿、足月新生儿、儿童和成人肝脏清除率的新成熟方程:对乙酰氨基酚及其代谢物的应用。
最近介绍了一个早产儿和足月新生儿到成人(PTNA)成熟方程来描述不同胎龄新生儿从出生到成年的肾小球滤过率成熟。本研究旨在评估新开发的PTNA方程与常用的成熟方法,如异速缩放(AS0.75)、AS0.75加经后年龄(PMA)的Emax (AS0.75 + PMA)方程和体重依赖指数方程(BDE)对扑热息痛(PCM)从早产儿和足月新生儿到成人的三条肝脏通路的成熟。对298名受试者(包括早产儿和足月新生儿、婴儿、儿童和成人)的PCM、PCM-葡萄糖糖苷(PCM- glu)、PCM-硫酸盐(PCM- sulf)和PCM-氧化代谢物(PCM- oxi)的血浆和尿液数据进行了人群药代动力学分析(观察数:6428)。分别评估PTNA、AS0.75、AS0.75 + PMA和BDE,以描述每种PCM代谢物的形成清除。结果表明,PTNA方程最能描述PCM-GLU的形成间隙,在统计和图形评价指标以及个体间变异性降低方面优于BDE和AS0.75 + PMA方程。对于PCM-SULF和PCM-OXI, PTNA方程也具有最好的性能,但改进幅度较小。最后的模型充分描述了PCM及其代谢物在亚群体之间的PK,如诊断图所示。总之,PTNA成熟方程最好地描述了PCM所有肝脏消除途径的成熟。因此,当来自早产儿、足月新生儿和大龄儿童的数据作为PK分析的一部分时,它可以潜在地应用于其他药物和途径。
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来源期刊
Journal of Clinical Pharmacology
Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-
自引率
3.40%
发文量
0
期刊介绍: The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.
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